Silanediols are recently developed analogues of the hydrated carbonyl that are effective as building blocks for low nanomolar inhibitors of metallo- and aspartic proteases. Serine proteases are also critical proteolytic enzymes whose inhibitors have broad therapeutic potential. The observation that Silanediols undergo facile, uncatalyzed exchange with methanol (initially observed with our HIV protease inhibitor) indicates that they have great potential as serine protease inhibitors as well. We will evaluate silandiols as inhibitors of serine and threonine proteases, studying five enzymes. Chymotrypsin is a benchmark and readily available serine protease that will allow us to rapidly establish Silanediols as serine protease inhibitors, including X-ray crystallography. Chymase is an important part of the immune response;the current understanding of the recognition sequence will allow us to quickly develop inhibitors. Cathepsin G is an enzyme involved in tissue remodeling with an overlap in specificity with chymase that will allow us to assess silanediol specificity. Granzyme B has a unique PI recognition requirement and is important in apoptosis. The 20S proteasome, a threonine protease, will test the limits of the Silanediols to interact with this important but sterically more hindered nucleophile. All targets except chymotrypsin are medically relevant, and silanediol inhibition will be further explored with enzyme X-ray crystallography (in collaboration with K. R. Acharya, Univ. of Bath)